Radiation Mitigation and Normal Tissue Stem Cells

项目摘要 该研究项目的长期目标是确定正常组织干细胞的机制， 最初存活暴露于辐射的细胞在体内扩张以保持组织完整性。这项提案的目的是 是揭示含有磺酰哌嗪活性基团的药物所观察到的缓解机制。我们 将研究应用这些药物后所见的正常组织干细胞库的重建是否 缓解剂对肠道和中枢神经系统（CNS）中的干细胞群有直接影响，或 通过提供允许干细胞扩增的微环境来介导。使用体外和体内模型 我们将研究这些药物对急性和晚期辐射损伤的直接和间接影响， 干细胞扩增和可塑性，并揭示导致辐射缓解的潜在信号事件。 具体地说，我们假设具有磺酰基哌嗪活性基团的辐射缓解剂，在 直接或间接影响肠道和CNS中的正常组织干细胞群 通过G蛋白偶联受体介导的信号传导。细胞效应的系统研究 化合物#15在缓解ARS和DEARE方面的作用，以及揭示潜在的机制将为以下方面奠定基础： 寻找和理解新型双重功能缓解剂，用于急性放射综合征（ARS）和延迟 急性辐射暴露（DEARE）。这将对该领域产生广泛的影响，因为它将揭示 正常组织干细胞上的常见靶点，可用于减轻多器官的辐射损伤 系统同时

PROJECT SUMMARY The long-term goal of this research project is to identify mechanisms by which normal tissue stem cells that initially survive exposure to radiation are expanded in vivo to maintain tissue integrity. The goal of this proposal is to uncover the mechanism of mitigation observed with drugs containing sulfonylpiperazine active groups. We will investigate whether the reconstitution of the normal tissue stem cell pool seen after application of these mitigators is a direct effect on the stem cell populations in the gut and central nervous system (CNS), or mediated by providing a microenvironment permissive for stem cell expansion. Using in vitro and in vivo model systems for acute and late radiation damage we will investigate direct and indirect effects of these drugs on stem cell expansion and plasticity and uncover the underlying signaling events that lead to radiation mitigation. Specifically, we hypothesize that radiation mitigators with sulfonylpiperazine active groups, identified in the previous funding period, affect normal tissue stem cell populations in the gut and CNS directly or indirectly through G-protein-coupled receptor-mediated signaling. The systematic study of the cellular effects of compound #15 in mitigating ARS and DEARE, and uncovering the underlying mechanisms will lay ground for finding and understanding novel dual function mitigators for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). This will have a wide impact on the field, as it will uncover common targets on normal tissue stem cells that can be used to mitigate radiation damage on multiple organ systems simultaneously.